1. Field of the Invention
The present invention relates to novel formulations of pharmaceutically-active agents and to novel devices and methods to obtain more rapid, enhanced and less variable dermal absorption of same, and more particularly to devices, formulations and methods for obtaining rapid, enhanced and less variable non-invasive anesthetization of the skin before painful medical procedures, such as injections, cannulations, skin grafts, biopsies, minor superficial surgeries, and the like.
2. State of the Art
The topical, dermal administration of drugs has long been known in the practice of medicine. (For purposes in this application, the terms "dermal" and "skin" relate to human skin and mucosa through or into which pharmaceutically-active agents are delivered. These pharmaceutically-active agents include but are not limited to topically, regionally, and systemically targeted drugs.) In the early 1970s, patents relating to advanced transdermal drug delivery systems began to issue. These devices were designed to hold one or more drugs and were affixed to the user such that the drug(s) contacted the user's skin for absorption of said drug(s).
In the early 1980s, more advanced systems were developed, such as U.S. Pat. No. 4,286,592 issued Sep. 1, 1981 to Chandrasekaran. This patent shows a bandage for administering drugs to a user's skin consisting of an impermeable backing layer, a drug reservoir layer composed of a drug and a carrier, and a contact adhesive layer by which the bandage is affixed to the skin.
It is known that elevated temperature can increase the absorption of drugs through the skin. It is thus conceivable that variable skin temperature can cause variable absorption of drugs in dermal drug delivery systems, which phenomenon could cause variable clinical profiles, such as variable onset time. To date, minimizing variability in skin drug absorption has been mainly through the use of rate limiting membranes, and no known prior art has attempted to minimize variability of dermal drug absorption by regulating the skin temperature. U.S. Pat. No. 4,898,592 issued Feb. 6, 1990 to Latzke et al. relates to a device for the application of heated transdermally absorbable active substances which includes a carrier impregnated with a transdermally absorbable active substance and a support. The support is a laminate made up of one or more polymeric layers and optionally includes a heat conductive element. This heat conductive element is used for distribution of the patient's body heat such that absorption of the active substance is enhanced. However, this device has no heat-generating element or function. Thus, the use of this heat conductive element to distribute body heat is not an efficient or reliable method of enhancing transdermal absorption by heating since the amount of body heat given off by a patient can vary depending on the ambient air temperature and the physical conditions of the patient.
U.S. Pat. No. 4,747,841, issued May 31, 1988 to Kuratomi et al., discloses a method and apparatus for moxibustion using a heat-generating element to heat and vaporize "moxa" for treatment of a patient's skin without leaving bum scars. Further, the focus of this patent is to achieve heat stimulation of the body and not to increase skin permeability. This teaching of heat stimulation of the body is contrary to the present invention, wherein stimulation of the body is to be minimized, particularly with pediatric patients. Finally, the reference teaches away from lower-temperature heating of the skin as not fully utilizing the moxa ingredients.
U.S. Pat. No. 4,230,105, issued Oct. 28, 1980 to Harwood, discloses a bandage with a drug and a heat-generating substance, preferably intermixed, to enhance the rate of absorption of the drug by a user's skin. Separate drug and heat-generating substance layers are also disclosed. Water must be applied to the bandage to activate the heating substance. In addition, the hydration process disclosed in this patent produces much less energy per unit mass than the heat-generating medium of the present invention. It also generates most of its heat in a relatively short time (in comparison to the medium employed in the present invention) and thus is not capable of providing stable heat for an extended duration. It is also incapable of regulating skin temperature desired range for extended duration. Once activated, heating temperature cannot be controlled.
U.S. Pat. No. 4,685,911, issued Aug. 11, 1987 to Konno et al., discloses a skin patch including a drug component, and an optional heating element for melting the drug-containing formulation if body temperature is inadequate to do so. The heating element is not substantially co-extensive with the drug reservoir, the latter being quite thick and thus not susceptible to even and rapid onset of heating.
It is desirable to noninvasively anesthetize the skin before some painful medical procedures, such as injections, cannulations, skin grafts, biopsies, minor superficial surgeries, and the like. EMLA.TM. (Eutectic Mixture of Local Anesthetics), a lidocaine-prilocaine formulation made by Astra, is widely used for these purposes. It is generally applied as a cream, then covered with a plastic bandage (cream-plus-cover system). EMLA's onset time (In this application, the term "onset time" is defined as the time between the start of the administration of the drug delivery system and the commencement of the desired clinical effect) in most cases ranges from about 45 to 90 minutes, or even longer, depending on the individual and the position and condition of the skin. This lengthy and quite variable onset time can cause prolonged and difficult to predict waiting on the part of patients, physicians and nurses in many situations.
EMLA's long and highly variable onset time is likely due to the two local anesthetic agents (lidocaine and prilocaine) used, as well as the lack of heating and control of skin temperature. Tetracaine is believed to be significantly better than lidocaine at producing full-depth skin anesthesia, but is subject to significant hydrolytic degradation.
A tetracaine/lidocaine eutectic mixture was discussed in U.S. Pat. No. 4,529,601 (the "'601 patent") issued Jul. 16, 1985 but not claimed.
McCafferty et al. in their publications and patents PCT/GB88/00416; GB2163956; Br. J. Anaesth. 60:64 (1988); 61:589 (1988), 62:17 (1989), 71:370 (1993)! mentioned a number of systems and formulations for non-invasive skin anesthesia, and discussed the advantages of a patch system over a cream-plus-cover system. They stated that an effective preparation should contain the minimum concentration of local anesthetic consistent with producing the desired clinical effect, and that onset times could not be reduced further by increasing the local anesthetic concentrations in their formulations after passing certain concentration.
In addition, none of prior art systems for noninvasive skin anesthesia have element or mechanism for regulating and increasing skin temperature. The low and uncontrolled skin temperature can lead to slow and widely variable onset time of anesthetic effect. That is because skin permeabilities of drugs are generally greatly influenced by skin temperature which is affected by ambient temperature and the user's physical condition, and thus can be quite variable if uncontrolled.
Therefore, it would be advantageous to develop an apparatus and method which achieves more rapid, enhanced and less variable dermal permeation of pharmaceuticals through the means of heating the skin and regulating the skin temperature, and which, more specifically when used with anesthetics, results in shorter onset times, achieves less variation in onset times by rapidly heating the skin temperature to a desired narrow range and maintaining the temperature in this range for a desirable length of time. It would also be advantageous to develop a novel product formulation which significantly improves the shelf-life of a product that contains a pharmaceutically-active agent(s) which is subject to hydrolytic degradation.